This is a revised application, for which we have now developed the mice that were requested in the previous reviews: floxed angiotensinogen and AT1a receptors. Therefore, all the critical reagents to the proposed studies are now available. Evidence has evolved, primarily in the last decade, demonstrating that the renin angiotensin system (RAS) has a profound effect on atherogenic mechanisms. However, many questions remain regarding the origin of the bioactive peptides and the mechanisms of the effects. Based on the findings of the previously funded period and others, the focus of the proposed research is to determine the relative importance of the systemic versus local RAS to the development of atherosclerosis. The central hypothesis of this proposal is that macrophage-derived RAS components are responsible for the local generation of angiotensin peptides that propagate atherosclerosis primarily via stimulation of AT1a receptors expressed on endothelial cells. To determine the validity of this hypothesis, the following specific aims are proposed. Aim 1: Determine the contribution of angiotensinogen from the liver (systemic) versus macrophages (local) to lesion size and characteristics of hypercholesterolemia-induced atherosclerosis. Aim 2: Determine the contribution of ACE1 and ACE2 expression on bone marrow-derived cells to the development of atherosclerotic lesion size and characteristics. Aim 3: Determine the cellular location of AT1a receptor expression that influences the atherogenic process. PUBLIC HEALTH RELEVANCE: Atherosclerotic diseases are the major cause of morbidity and mortality in the US population. Therefore, investigations to prevent these diseases have vast public health implications.